DTIC ADA466563: PCBs Alter Dopamine Mediated Function in Aging Workers

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Award Number: DAMD17-02-1-0173

TITLE: PCBs Alter Dopamine Mediated Function in Aging Workers

PRINCIPAL INVESTIGATOR: Richard F. Seegal, Ph.D.

CONTRACTING ORGANIZATION: Health Research Incorporated
Rensselaer, NY 12144-3456

REPORT DATE: January 2007

TYPE OF REPORT: Annual

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Fort Detrick, Maryland 21702-5012

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PCBs Alter Dopamine Mediated Function in Aging Workers
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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

TABLE OF CONTENTS

Cover...........................................................................................................................................1

SF 298.........................................................................................................................................2

Table of Contents .......................................................................................................................3

Introduction.................................................................................................................................4

Body............................................................................................................................................4

Key Research Accomplishments..............................................................................................12

Reportable Outcomes................................................................................................................12

Conclusions...............................................................................................................................13

References...............................................................................................................................NA

Appendices................................................................................................................................13
DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

INTRODUCTION

The major hypotheses to be tested in this project are that high-level occupational
exposure of former capacitor workers to polychlorinated biphenyls (PCBs) will result in
reductions in: (i) performance on neuropsychological and neurological tests that reflect the
historic PCB body burden of the individual and (ii) the number of dopamine (DA) terminals in
the basal ganglia.
Aging former capacitor workers, previously employed at capacitor manufacturing
facilities located approximately fifty miles north of Albany, NY, have undergone
neuropsychological and neurological exams, completed a comprehensive occupational,
residential and dietary questionnaire, had blood drawn to measure serum thyroid hormone and
PCB concentrations, and undergone a non-invasive test to determine bone lead concentrations in
Albany, NY. This latter measure will reduce the likelihood of confounding the neurological
effects of prior PCB exposure with the neurological effects of prior lead exposure. Finally,
approximately 40% of the subjects have participated in a second portion of the study that uses
brain β-CIT SPECT imaging to determine whether prior occupational exposure to PCBs reduces
the number of basal ganglia DA terminals. Imaging took place at the Institute for
Neurodegenerative Disorders in New Haven, CT under the supervision of Dr. Kenneth Marek.
In order to test the above hypotheses we have gathered a team of internationally
recognized experts in the epidemiology of environmental and occupational exposure to PCBs,
the neurology of movement disorders and Parkinson’s Disease, the assessment of toxicant-
induced deficits in neuropsychological function, measurement of serum PCB concentrations,
non-invasive determination of bone lead concentrations, and brain imaging of central DA
neurons and their relationship to movement disorders, including Parkinson’s Disease.

STUDY INVESTIGATORS
Albany, NY Based Testing
Richard F. Seegal - Wadsworth Center, New York Sate Dept. of Health (NYSDOH):
Principal Investigator
Edward F. Fitzgerald – University at Albany, School of Public Health: Epidemiologist
Lenore J. Gensburg - Center for Environmental Health, NYSDOH:
Tracing, Screening, Residential, Occupational, Dietary and Medical Histories
Eric S. Molho, Donald S. Higgins - Albany Medical Center: Neurological Assessment
Stewart A. Factor - Emory University: Neurology Consultant
Robert J. McCaffrey - University at Albany: Neuropsychological Assessment
Richard F. Haase - University at Albany: Biostatistician
Mary S. Wolff - Mount Sinai School of Medicine: Serum PCB Analyses
Andrew C. Todd - Mount Sinai School of Medicine: Bone Lead Determination
Patrick Parsons - Wadsworth Center, NYSDOH: Bone Lead Determination
New Haven, CT Based Testing
Kenneth Marek, John P. Seibyl, Danna Jennings - Institute for Neurodegenerative
Disorders: ß-CIT SPECT Brain Imaging

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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

PROGRESS IN FISCAL YEAR 2006

The following narrative provides descriptions of the progress we have made in the fifth
year of the project (fourth year of data collection)―a period in which we have been actively
engaged in both data collection and analysis of the resulting data. At the conclusion of data
collection in mid April 2006 we had tested 241 subjects in Albany which represents 97% of our
projected goal of testing 248 subjects. In addition, 89 of those subjects traveled to New Haven,
CT to undergo β-CIT imaging to estimate the density of basal ganglia dopamine transporters.
This number represents 93% of our stated goal of testing 96 subjects. Given the distance of
travel (2.5 hours) and the necessity of committing two days for the imaging, we are particularly
proud of having almost reached this latter goal.
A significant effort has been, and continues to be made, to analyze the vast amounts of
data that were generated during active data collection. In addition to collecting the major
dependent variables (neurological, neuropsychological, β-CIT, bone lead, thyroid hormone and
serum PCB concentrations) we have also collected extensive information from a 2-2.5h
interview that will provide important information on potential confounders that may influence
the dependent variable outcomes listed above. A list of these potential confounders that are
currently being examined is included in Appendix 1.
Interview data pertaining to demographic characteristics, medical history, medication use,
smoking and alcohol consumption and diet (including sport fish) and other relevant variables
have been double data entered and subdivided into subject-specific SAS datasets. Edit programs
have been developed to detect out-of-range and logical inconsistencies and any errors have been
corrected. The occupational histories have been reviewed by two certified industrial hygienists
who evaluated each job for the likelihood of exposure to PCBs, lead, mercury, and pesticides,
using a four point scale. Each job has also been classified using Standard Industrial and
Occupation codes and medications have been coded according to the American Hospital
Formulary Service.
Table I provides information on the basis demographics of individuals who were
contacted and asked to participate in the Capacitor Worker Study.

TABLE I: Albany, NY Testing, Participation of Potential
Subjects at the End of Recruitment 4/19/06 (n=490)

YES: 241 NO: 249
GENDER
Male 129 53.53% 104 41.77%
Female 112 46.47% 145 58.23%

AGE
50s 91 37.76% 87 34.94%
60s 77 31.95% 67 26.91%
70s 59 24.48% 66 26.51%
80-90s 14 5.81% 29 11.65%

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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

Following testing in Albany, subjects were asked if they wished to participate in the
SPECT β-CIT imaging portion of the study carried out by Dr. Marek’s group at the Institute for
Neurodegenerative Disorders in New Haven, CT. Despite the fact that these procedures require
a two day stay in New Haven and the injection of a radio-labeled tracer, we were able to test
93% of the subjects we had originally stated we would test. These data are presented in Table II.

TABLE II: New Haven, CT Testing, Participation of Potential Subjects at
the End of Recruitment 8/31/06 (n=241)
YES: 89 NO: 128 Not Contacted: 24
GENDER
Male 50 56.18% 67 52.34% 12 50.00%
Female 39 43.82% 61 47.66% 12 50.00%

AGE
50s 34 38.20% 46 35.94% 11 45.83%
60s 38 42.70% 32 25.00% 7 29.17%
70s 13 14.61% 40 31.25% 6 25.00%
80-90s 4 4.49% 10 7.81% 0 0.00%

The lower participation rates of subjects in their 70s and 80s reflect the difficulties in
both traveling to New Haven, CT and committing to a two night stay. We feel that participation
rates would have been lower if we had not provided round-trip limousine service.
Table III presented below provides a summary of tracing, screening and recruitment for
individuals through April 19, 2006. Tracing refers to the procedures carried out to identify and
locate individuals who potentially could take part in the study, while screening refers to the
procedures carried out by staff at the Center for Environmental Health (a part of the New York
State Department of Health) to determine if the individuals were medically eligible. A list of
conditions that made subjects medically ineligible is presented in Appendix 2. If eligible, the
subjects’ names were sent to the Study Coordinator who contacted them to more completely
describe the test protocols and schedule their visits to Albany.
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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

TABLE III: Subjects Selected from Cohort (n=6798) Through the
End of Recruitment 4/19/06
Tracing Results Entered Tracing: 2920
Dead 885 30.31%
Out of Area 245 8.39%
Too Young 0 0.00%
Could not be Located 562 19.25%
Eligible for Screening 1181 40.45%
Not Traced 47 1.61%
Screening Results Entered Screening: 1181
Refused 232 19.64%
Ineligible-Medical 341 28.87%
Ineligible-Non-Medical 65 5.50%
Eligible for Recruitment 491 41.57%
Not Screened 52 4.40%
Albany Testing:
Recruitment Results Entered Recruitment: 491
Participated 241 49.08%
Refused 249 50.71%
Remaining* 1 0.20%
New Haven Testing:
Recruitment Results Entered Recruitment: 241
Participated + Scheduled (5) 89 36.93%
Refused 128 53.11%
Other** 24 9.96%
*Not scheduled as of the end of the study.
**Cancelled, ineligible, no contact, could not be scheduled.

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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

Table IV provides a summary of the final subject participation in both the Albany, NY
and New Haven, CT portions of the study from inception through 19 April 2006.

TABLE IV: Summary of Subject Participation at the
End of Recruitment 4/19/06

All Subjects
Albany Participation
Yes, Participated 241 49%
Not Contacted 1 <1%
Refused 249 51%
TOTAL 491 100%

New Haven Participation
Yes, Participated 89 37%
Scheduled/Not Tested 2 1%
Not Contacted 12 5%
Ineligible 5 2%
Cancelled 5 2%
Refused 128 53%
TOTAL 241 100%

Measurement of Serum PCB Concentrations
Dr. Mary Wolff, of the Mt. Sinai School of Medicine, has analyzed serum PCB
concentrations from the former capacitor workers using glass capillary gas chromatographic
techniques. Data includes not only congener specific determination of current serum PCB
concentrations, obtained when the subjects traveled to Albany, but also, for those individuals for
whom we have archived sera, re-analysis using the same analytical procedures described in the
grant application. The availability of both current and archived sera PCB levels, determined in
the same laboratory using the same analytical techniques, will allow us to more precisely
estimate historic serum PCB levels for those individuals for whom we do not have archived sera.
The data presented below represents PCB analyses from 240 subjects broken down by
age (decade) and gender. It is noteworthy that the serum PCB levels remain elevated (average
PCB levels in non-occupationally-exposed individuals are approximately 2-3 ppb) more than
twenty-five years after occupational exposure ceased. Although we chose to present only total
PCB concentrations (a sum of lightly and heavily chlorinated congeners), subsequent analyses,
particularly for levels of lightly chlorinated congeners that have short half-lives, will allow us to
discriminate between occupational and more recent recreational and/or residential exposures.

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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

Figure 1. Total Current Serum PCB Levels (mean + sem)
25
) M (n=129)
b
p F (n=111)
p 20 (n=8)
N ( (n=5)
O)
m (n=32)
ATIru 15 (n=27)
NTRnt Se (n=42)
CErre 10 (n=50)
Nu (n=35)
OC
(
C (n=41)
B 5
C
P
0
50-59 60-69 70-79 80-89
AGE

Measurement of Bone Lead Concentrations by K-Shell X-Ray Fluoresence
Dr. Andrew Todd of Mount Sinai supervised the in vivo measurement of lead in bone in
Albany and analyzed the raw data (in electronic form) generated with the bone lead measurement
system. Mount Sinai personnel also provided consultation on all aspects of the X-ray
Fluorescence bone lead measurement system, including regular and ad hoc consultation, as
required, on the quality of spectra acquired, the control and use of the measurement system and
the reliability of the analytical results in order to provide both the most precise and the most
reliable bone-lead data possible.
Mount Sinai personnel also supervised the Albany XRF operators in the daily operation
of the XRF measurement system with regard to its maintenance, calibration, optimization and
quality control protocol and have provided expertise on the optimization of the measurement
system with regard to operational parameters of the spectroscopy electronics (viz. rise time, flat-
top, etc.).
All calibration and human measurement XRF data have been electronically transmitted to
the Mount Sinai XRF Laboratory for analysis. The analyses of the data received to date have
been completed. Analyses of new data are being performed as they arrive. A total of 230 study
participants have had their bone lead measured and analyzed; these bone lead data are presented
in Figure 2 below and demonstrate a significant association between tibia lead concentrations in
men, but not in women.

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DAMD17-02-1-0173 Annual Report – January 2007
PCBs Alter Dopamine Mediated Function in Aging Workers Seegal, Richard F.

Figure 2. Tibia Lead (Pb) Concentrations by Age and Gender
45 45
al) 40 MALE (n=123) al) 40 FEMALE (n=107)
ner 35 ner 35
mi 30 r2 = 0.20 mi 30
e p < 0.001 e
n 25 n 25
g bo 20 NAvoermraagle g bo 20 NAvoermraagle
cg/ 15 cg/ 15 r2 = 0.002
m 10 m 10 p = 0.66
Pb ( 5 Pb ( 5
A 0 A 0
BI BI
TI -5 TI -5
-10 -10
50 60 70 80 90 50 60 70 80 90
AGE (years) AGE (years)

Measurement of Brain Dopamine Transporter by β-CIT SPECT Imaging
Preliminary analysis of the data yielded a significant statistical relationship between
dopamine transporter density measured by β-CIT SPECT imaging and current serum total PCB
concentrations which was observed only in female former capacitor workers. This measurement
represents the average uptake of the radio-labeled ligand [123I]β-CIT in the putamen and caudate
of male and female former exposed workers measured by SPECT imaging, providing an in-vivo
measure of dopamine transporter density. Total PCB levels were measured in serum from the
subjects at the time of imaging. The significant negative relationship seen only in female
workers—all who were postmenopausal—has allowed us to formulate a hypothesis that estrogen
withdrawal increases risk of basal ganglia dopamine dysfunction only in women (see also
Conclusion). As noted in Appendix 3 this gender difference remains when age was controlled
for statistically.
Figure 3. Dopamine Terminal Density Measured by β-CIT SPECT Imaging
as a Function of Current Serum PCB Concentrations
8 8
E Male r2 = 0.01 E Female r2 = 0.34
K K
A p = 0.42 A p < 0.001
T 7 n=50 T 7 n=39
P P
U U
T T
CI CI
-β 6 -β 6
L L
A A
T T
A 5 A 5
RI RI
T T
S S
4 4
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 0.0 0.5 1.0 1.5 2.0 2.5
log CURRENT TOTAL PCBs log CURRENT TOTAL PCBs
10